Tissue inhibitor of metalloproteinase‐3 (TIMP‐3) gene is methylated in the development of esophageal adenocarcinoma: Loss of expression correlates with poor prognosis

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Abstract
Amongst involvement in diverse physiological and pathological processes, TIMP‐3 may have an important role in tumour development, growth and metastasis by interaction with metalloproteases in the extracellular matrix. We studied the role and prognostic effect of TIMP‐3 in esophageal adenocarcinoma (EADC). TIMP‐3 gene methylation and TIMP‐3 mRNA expression were analysed in 5 esophageal cell lines and 24 resected EADCs. TIMP‐3 protein expression was examined in the 5 cell lines and 79 resected EADCs with known clinicopathological features. TIMP‐3 methylation signal was only detected in the OE33 EADC cell line. In tissues, 0% of case‐matched normal, 72% of BE and 90% of EADC were positive for methylation. TIMP‐3 mRNA was detected in all the cell lines and normal, metaplastic and tumour tissues. TIMP‐3 protein was localised to the cytoplasm in cell lines and tissues. Demethylating treatment of OE33 increased protein expression. At the invading edge of tumours, protein staining was equal to, or reduced, compared to normal tissues. Reduction of protein expression was associated with disease stage (p = 0.046) and poor patient survival (OR 2.1, 95% CI 1.2–3.5, p = 0.007). Mean survival time was halved in patients with reduced tumour TIMP‐3 expression, from 49 to 24 months. These studies have demonstrated association between methylation of the TIMP‐3 gene and BE and EADC. Reduced expression of TIMP‐3 protein in EADC is associated with increased tumour invasiveness and reduced patient survival.